Comparative chemoreactome analysis of mexidol
Abstract
The paper presents the results of chemorectome modeling of the pharmacological effects of ethylmethylhydroxypyridine succinate (mexidol) as compared to control molecules (choline alfoscerate, piracetam, glycine, semax). Chemoreactome analysis showed that mexidol may be (1) an agonist of acetylcholine and GABA-A receptors; (2) an anti-inflammatory agent, the effects of which are carried out by inhibiting the synthesis of pro-inflammatory prostaglandins; (3) a neurotrophic agent with neuroprotective properties; (4) a coagulation inhibitor; (5) a diabetes medication and (6) a hypolipidemic agent. From the “control” molecules mexidol is distinguished by a more pronounced safety profile (a lower impact on serotonin, dopamine and adrenergic receptors, a lesser degree of interaction with the potassium channels of the heart, with the MAO enzyme and with the P450 cytochromes). The results of the chemoreactome modeling allowed us to formulate the mechanisms of action of mexidol at the molecular level.
About the Authors
I. J. Torshin
ФГАОУ ВО «Московский физико-технический институт»
Russian Federation
Russian Federation
O. A. Gromova
ФГБОУ ВО «Ивановская государственная медицинская академия» Минздрава России
Russian Federation
Russian Federation
I. S. Sardaryan
ФГБОУ ВО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава России
Russian Federation
Russian Federation
L. E. Fedotova
ФГБОУ ВО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава России
Russian Federation
Russian Federation
V. A. Semenov
ФГАОУ ВО «Московский физико-технический институт»; ФГБОУ ВО Кемеровская государственная медицинская академия Минздрава РФ
Russian Federation
Russian Federation
References
1. Об утверждении перечней жизненно необходимых и важнейших лекарственных препаратов для медицинского применения на 2016год. Распоряжение от 26 декабря 2015 года №2724-р. http://govemment.ru/ docs/21361/
2. SA. Rumyantseva A.; I. Fedin; О. N. Sokhova. Antioxidant Treatment of Ischemic Brain Lesions. Neuroscience and Behavioral Physiology, 2012, 42 (8): 842-845. doi:10.1007/sll055-012-9646-3.
3. Косенко В.Г., Карагезян Е.А., Лунева Л.В., Смоленко Л.Ф. Применение мексидола в психиатрической практике. Журнал неврологии и психиатрииим. С. С. Корсакова. 2006; 6.
4. Volchegorskii I.A., Miroshnichenko I.Y., Rassokhina L.M., Faizultin R.M., Malkin M.P., Pryakhina K.E., Kalugina A.V. Comparative analysis of the anxiolytic effects of 3-hydroxypyridine and succinic acid derivatives. Bull Exp Biol Med. 2015 Apr; 158 (6): 756-61. doi: 10.1007/sl0517-015-2855-3.
5. Torshin I.Yu. Bioinformatics in the post-genomic era: physiology and medicine. Nova Biomedical Books, NY, USA (2007), ISBN 1-60021-752-4.
6. Журавлёв Ю.И., Рудаков К.В., Торшин И.Ю. Алгебраические критерии локальной разрешимости и регулярности как инструмент исследования морфологии аминокислотных последовательностей. Труды МФТИ. 2011; 3: 4: 67-76.
7. Рудаков К.В., Торшин И.Ю. Об отборе информативных значений признаков на базе критериев разрешимости в задаче распознавания вторичной структуры белка. ДАН. 2011; 441: 1: 1-5.
8. Журавлев Ю.И. Об алгебраическом подходе к решению задач распознавания или классификации. Проблемы кибернетики. Вып. 33. М.: Наука, 1978; 5-68.
9. Торшин И.Ю., Громова O.A. Экспертный анализ данных в молекулярной фармакологии. М.: Изд. МЦНМО, 2012; 768.
10. Bolton E., Wang Y., Thiessen P.A., Bryant S.H. PubChem: Integrated Platform of Small Molecules and Biological Activities. Chapter 12 IN Annual Reports in Computational Chemistry, blume 4, American Chemical Society, Washington, DC, 2008 Apr. (pubchem.ncbi.nlm.nih.gov).
11. Wishart D.S., Tzur D., KnoxC., Eisner R., Guo A.C., Young N., Cheng D., Jewell K., Arndt D., Sawhney S., Fung C., Nikolai L., Lewis M., Coutouly M.A., Forsythe L., Tang P., Shrivastava S., Jeroncic K., Stothard P., Amegbey G., Block D., Hau D.D., Wagner J., Miniaci J., Clements M., Gebremedhin M., Guo N., Zhang Y., Duggan G.E., Macinnis G.D., Weljie A.M., Dowlatabadi R., Bamforth F., Clive D., Greiner R., Li L., Marrie Т., Sykes B.D., Vogel H.J., Querengesser L. HMDB: the Human Metabolome Database. Nucleic Acids Res. 2007; 35 (Databas:D521-D526.
12. Olianas M.C., Dedoni S., Onali P. Protection from interferon-beta-induced neuronal apoptosis through stimulation of muscarinic acetylcholine receptors coupled to ERK1/2 activation. Br J Pharmacol. 2016; 173 (19): 2910-2928 doi.
13. Lin N.H., Gunn D.E., Ryther K.B., Garvey D.S., Donnelly-Roberts D.L., Decker M.W., Brioni J.D., Buckley M.J., Rodrigues A.D., Marsh K.G., Anderson D.J., Buccafusco J.J., Prendergast M.A., Sullivan J.P., Williams M., Americ S.P., Holladay M.W.Structure-activity studies on 2-methyl-3-(2(S)-pyrrolidinylmethoxy) pyridine (ABT-089): an orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognition-enhancing properties. J Med Chem. 1997; 40 (3): 385-390.
14. Nakamura M., Jang L.S. Muscarinic M4 receptors regulate GABAergic transmission in rat tuberomammillary nucleus neurons. Neuropharmacology. 2012; 63 (6): 936-44 doi.
15. Vandevrede L., Tavassoli E., Luo J., Qin Z., Yue L., Pepperberg D.R., Thatcher G.R. Novel analogues of chlormethiazole are neuroprotective in four cellular models of neurodegeneration by a mechanism with variable dependence on GABA(A) receptor potentiation. Br J Pharmacol. 2014; 171 (2): 389-402 doi.
16. Avolio E., Mahata S.K., Mantuano E., Meie M., Alo R., Facciolo R.M., Talani G., Canonaco M.Antihypertensive and neuroprotective effects of catestatin in spontaneously hypertensive rats: interaction with GABAergic transmission inamygdalaandbrainstem. Neuroscience. 2014; 270: 48-57 doi.
17. Young W.Spinal cord regeneration. Cell Transplant. 2014; 23 (4-5): 573-611 doi.
18. Gaikwad A.B., Viswanad B., Ramarao P. PPAR gamma agonists partially restores hyperglycemia induced aggravation of vascular dysfunction to angiotensin II in thoracic aorta isolated from rats with insulin resistance. Pharmacol Res. 2007; 55 (5): 400-7 Epub 2007 Feb.
19. Braga R.C., Alves V.M., Silva M.F., Muratov E., Fourches D., Tropsha A., Andrade C.H. Tuning HERG out: antitarget QSAR models for drug development. CurrTop Med Chem. 2014; 14 (11): 1399-1415.
20. Sanguinetti M.C., Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature. 2006; 440 (7083): 463-469.
21. Palee S., Apaijai N., Shinlapawittayatorn K., Chattipakorn S.C., Chattipakorn N. Acetylcholine Attenuates Hydrogen Peroxide-Induced Intracellular Calcium Dyshomeostasis Through Both Muscarinic and Nicotinic Receptors in Cardiomyocytes. Cell Physiol Biochem. 2016; 39 (1): 341-9 doi.
22. Dorszewska J., Florczak J., Rozycka A., Jarosz.ewska-Kolecka J., Trzeciak W.H., Kozubski W. Polymorphisms of the CHRNA4 gene encoding the alpha4 subunit of nicotinic acetylcholine receptor as related to the oxidative DNA damage and the level of apoptotic proteins in lymphocytes of the patients with Alzheimer’s disease. DNA Cell Biol. 2005; 24 (12): 786-794.
23. Li Y., King M.A., Meyer E.M. alpha7 nicotinic receptor-mediated protection against ethanol-induced oxidative stress and cytotoxicity in PC12 cells. Brain Res. 2000; 861 (1): 165-167.
24. Stegemann A., Bohm M. The alpha7 nicotinic acetylcholine receptor agonist tropisetron counteracts UVA-mediated oxidative stress in human dermalfibroblasts. Exp Dermatol. 2016; Exp Dermat: 101111/exdl3220.
25. Shan K.R., Qi X.L., Long Y.G., Nordberg A., Guan Z.Z. Decreased nicotinic receptors in PC12 cells and rat brains influenced by fluoride toxicity--a mechanism relating to a damage at the level in post-transcription of the receptorgenes. Toxicology. 2004; 200 (2-3): 169-177.
26. Han Z., Shen F., He Y., Degos V., Camus M., Maze M., Young W.L., Su H. Activation of alpha-7 nicotinic acetylcholine receptor reduces ischemic stroke injury through reduction of pro-inflammatory macrophages and oxidative stress. PLoS One. 2014; 9 (8): el05711 doi.
27. Navarro E., Buendia I., Parada E., Leon R., Jansen-Duerr P., Pircher H., Egea J., Lopez. M.G. Alpha7 nicotinic receptor activation protects against oxidative stress via heme-oxygenase I induction. Biochem Pharmacol. 2015; 97 (4): 473-81 doi.
28. Gao Z., Zhang H., Liu J., Lau C.W., Liu P., Chen Z.Y., Lee H.K., Tipoe G.L., Но H.M., Yao X., Huang Z.Cyclooxygenase-2-dependent oxidative stress mediates palmitate-induced impairment of endothelium-dependent relaxations in mouse arteries. Biochem Pharmacol. 2014; 91 (4): 474-82 doi.
29. Nishizaki Т., Matsuoka Т., Nomura Т., Sumikawa K. Modulation of ACh receptor currents by arachidonic acid. Brain Res Моl Brain Res. 1998; 57 (1): 173-179.
Review
For citations:
Torshin I.J., Gromova O.A., Sardaryan I.S., Fedotova L.E., Semenov V.A. Comparative chemoreactome analysis of mexidol. Pharmacokinetics and Pharmacodynamics. 2016;(4):19-30. (In Russ.)
Views:
1056
Email this article 